1. Field of Invention
The present invention relates to methods and compositions for treating hepatitis virus infections, especially hepatitis B virus infections, in mammals, especially humans. The methods comprise administering glucamine compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/-immunostimulating agents. Such combinations of anti-hepatitis viral agents show unexpected efficacy in inhibiting replication and secretion of hepatitis viruses in cells of mammals infected with these viruses.
2. Background of Invention
Over half the biologically important proteins are glycosylated and that glycosylation may vary with disease. Based upon this information, the use of drugs to control of glycosylation patterns, glycoforms, changes or rates of change will have a biochemical effect and may provide a beneficial therapeutic result. Control of glycolipid and glycoprotein sugar patterns as well as their synthesis and degradation leads to basic physiological effects on mammals including humans, agricultural animals and pets. Possibly, this is through influences on, for example, N-linked glycans, O-linked glycans, glucosoaminoglycans, glycosphingolipids, glycophospholipids, lectins, immuneoglobulin molecules, antibodies, glycoproteins and their biochemical intermediates or conversion products. Modification of glycosalation site occupancy influences receptor and enzyme binding site specificity, selectivity, capacity, protein folding, enzyme activity, kinetics and energetics. Glycosidase and glycosyltransferase systems are two biochemical mechanisms that are suggested to affect such systems (Dwek, Raymond A., Glycobiology: Toward Understanding the Function of Sugars, Chemical Reviews, 96, 683-720(1996).
Iminosugars are anti-viral drugs that can induce the inhibition of viral interactions with and within mammalian cells such as attachment to cells, penetration of cells, maturation within cells and release from cells. The mechanism involved may be glucosidase inhibition, glycosyl transferase inhibition or others as discussed above.
Hepatitis B Virus (HBV, HepB) is a causative agent of acute and chronic liver disease including liver fibrosis, cirrhosis, inflammatory liver disease, and hepatic cancer that can lead to death in some patients (Joklik, Wolfgang K., Virology, Third Edition, Appleton and Lange, Norwalk, Conn., 1988 (ISBN 0-8385-9462-X)). Although effective vaccines are available, there are still more than 300 million people worldwide, i.e., 5% of the world""s population, chronically infected with the virus (Locarnini, S. A., et. al., Antiviral Chemistry and Chemotherapy (1996) 7(2) :53-64). Such vaccines have no therapeutic value for those already infected with the virus. In Europe and North America, between 0.1% to 1% of the population is infected. Estimates are that 15% to 20% of individuals who acquire the infection develop cirrhosis or another chronic disability from HBV infection. Once liver cirrhosis is established, morbidity and mortality are substantial, with about a 5-year patient survival period (Blume, H., E., et.al., Advanced Drug Delivery Reviews (1995) 17:321-331). It is therefore necessary and of high priority to find improved and effective anti-hepatitis therapies (Locarnini, S. A., et. al., Antiviral Chemistry and Chemotherapy (1996) 7(2): 53-64)
Other hepatitis viruses significant as agents of human disease include Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis Delta, Hepatitis E, Hepatitis F, and Hepatitis G (Coates, J. A. V., et.al., Exp. Opin. Ther. Patents (1995) 5(8):747-756). Hepatitis C infection is also on the increase and effective treatments are needed. In addition, there are animal hepatitis viruses that are species-specific. These include, for example, those infecting ducks, woodchucks, cattle and mice.
Glucamine (also known as 1-deoxynojirimycin, DNJ) and its N-alkyl derivatives (together, xe2x80x9cimino sugarsxe2x80x9d) are known inhibitors of the N-linked oligosaccharide processing enzymes alpha glucosidase I and II (Saunier et al., J. Biol. Chem. (1982) 257:14155-14161 (1982); Elbein, Ann. Rev. Biochem. (1987) 56:497-534). As glucose analogs, they also have potential to inhibit glucose transport, glucosyl-transferases, and/or glycolipid synthesis (Newbrun et al., Arch. Oral Biol. (1983) 28: 516-536; Wang et al., Tetrahedron Lett. (1993) 34:403-406). Their inhibitory activity against glucosidases has led to the development of these compounds as anti-hyperglycemic agents and antiviral agents. See, for example, PCT International Publication WO 87/03903 and U.S. Pat. Nos. 4,065,562; 4,182,767; 4,533,668; 4,639,436; 4,849,430; 4,957,926; 5,011,829; and 5,030,638.
Glucosidase inhibitors such as N-alkyl-glucamine compounds wherein the alkyl group contains between three and six carbon atoms have been shown to be effective in the treatment of Hepatitis B infection (PCT International Publication WO 95/19172). For example, N-(n-butyl)-deoxynojirimycin (N-butyl-DNJ; N-(n-butyl)-1-5-dideoxy-1,5-imino-D-glucitol) is effective for this purpose (Block, T. M., Proc. Natl. Acad. Sci. USA (1994) 91:2235-2239; Ganem, B. Chemtracts: Organic Chemistry (1994) 7(2), 106-107). N-butyl-DNJ has also been tested as an anti-HIV-1 agent in HIV infected patients, and is known to be well tolerated. Another alpha glucosidase inhibitor, deoxynojirimycin (DNJ), has been suggested as an antiviral agent for use in combination with N-(phosphonoacetyl)-L-aspartic acid (PALA) (WO 93/18763). However, combinations of N-substituted-imino-D-glucitol derivatives and other antiviral agents for the treatment of hepatitis virus infections have not been previously disclosed or suggested. From results obtained in a woodchuck animal model of hepatitis virus infection, Block et al. ((1998) Nature Medicine 4(5):610-614) suggested that glucosidase inhibitors such as N-nonyl DNJ, which interfere with specific steps in the N-linked glycosylation pathway of hepatitis virus glycoproteins, may be useful in targeting glycosylation processing as a therapeutic intervention for hepatitis B virus.
Compounds such as N-butyl-DNJ (N-butyl-deoxynojirimycin) and N-butyl-DGNJ (N-butyl-desoxynogalactonojirimycin) are reported as treatments of lysosomal storage diseases such as Tay-Sachs disease, Gauchers disease and related ailments. In addition, treatment of cholera has been reported (U.S. Pat. No. 5,399,567) via inhibition of the synthesis of glycolipids (U.S. Pat. No. 5,472,969). Inhibition of glycosyl transferase or glycosidase enzymes that affect the catabolism and metabolism of phopholipids, sphingolipids, cerebrosides, gangliosides by or and within mammalian cells or interference with such biochemical processes as attachment to cells, penetration of cells and/or release from cells. In any event, treatments for these diseases are badly needed since xe2x80x9cWith rare exceptions a treatment of these often lethal diseases is not possible to date.xe2x80x9d (Kolter, T and Sandhoff, K, Inhibitors of Glycosphingolipid Biosynthesis, Chemical Society Reviews, 371-381 (1996), WO 98/02161
The use of N-butyl-1,5-dideoxy-1,5-imino-D-glucose and certain other imino-glucose compounds for the treatment of diseases caused or induced by human immunodeficincy virus (HIV), cytomeglovirus CMV), hepatitis virus, respiratory syncytial virus (RSV) and herpes virus (HSV) infection has been reported. Again, treatment of these infections is desirable and an important public goal.
Reverse transcriptase inhibitors, including the class of nucleoside and nucleotide analogs, were first developed as drugs for the treatment of retroviruses such as human immunodeficiency virus (HIV), the causative agent of AIDS. Increasingly, these compounds have found use against other viruses, including both RNA and DNA viruses, via viral screening and chemical modification strategies. Nucleoside and nucleotide analogs exert their antiviral activities by inhibiting the corresponding DNA and RNA polymerases responsible for synthesis of viral DNA and RNA, respectively. Because viruses contain different forms of polymerases, the same nucleoside/nucleotide compound can have a dramatically different effect against different viruses. For example, lamivudine (3TC) appears to be useful against HBV infection, whereas zidovudine (AZT) appears to have little use against the same virus (Gish, R. G., et al., Exp. Opin. Invest. Drugs (1995) 4(2):95-115).
AZT is an example of a nucleoside/nucleotide analog that can effect glycosylation processes at clinically achievable concentrations rather than interfere with DNA replication or protein synthesis (Yan, J., et.al., J. Biol. Chem., 270, 22836 (1995).
Toxicity has been significant with some nucleoside analog antivirals. For example, clinical tests on the use of the nucleoside analog fialuridine (FIAU) for treatment of chronic hepatitis B were suspended recently due to drug-related liver failure leading to death in some patients. Consequently, there is still a need for safer drug regimens for the treatment of hepatitis B infections and hepatitis (Mutchnick, M. G., et. al., Antiviral Research (1994) 24:245-257).
Immunomodulators/immunostimulators such as interferon alpha and other cytokines have been used for the treatment of HBV infection with promising results. Unfortunately, the response rates are lower than desired. Interferon treatment is currently approved by the FDA for the treatment of Hepatitis B. Other immune system-affecting drug candidates are presently being investigated. These include thymic peptides for use in the treatment of chronic hepatitis B (CHB), isoprinosine, steroids, Schiff base-forming salicylaldehyde derivatives such as Tucaresol, levamisol, and the like (Gish, R. G., et.al., Exp. Opin. Invest. Drugs (1995) 4(2):95-115; Coates, J. A. V., et.al., Exp. Opin. Ther. Patents (1995) 5(8):747-765).
As noted above, the use of the substituted-glucamine compounds and derivatives thereof disclosed herein alone, or in combination with other anti-hepatitis virus compounds has, to the present inventor""s knowledge, neither been suggested nor disclosed. The use of two or more anti-viral agents to provide improved therapy for the treatment of hepatitis B virus and hepatitis C virus infections is desirable due to the morbidity and mortality of the disease. Combination therapy is also desirable since it can reduce toxicity in patients as it enables the physician to administer lower doses of one or more of the drugs being given to a patient. Combination therapy can also help to prevent the development of drug resistance in patients (Wiltink, E. H. H., Pharmaceutish Weekblads Scientific Edition (1992) 14(4A):268-274). The result of an improved efficacy configuration combined with a relative lack of toxicity and development of resistance would provide a much improved drug treatment profile.
Substituted glucamine compounds disclosed herein are effective in treating hepatitis virus infections. Furthermore, the use of these compounds in combination with nucleoside or nucleotide antiviral compounds, or combinations thereof, and/or immunomodulators/immunostimulants, results in unexpectedly greater anti-hepatitis virus effectiveness of the compounds compared to the combined antiviral activities expected of the individual compounds alone. Whether this is due to different mechanisms of action of the different classes of drugs employed or some other biological phenomenon is presently unclear.
Accordingly, in a first aspect, the present invention provides a method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal an anti-hepatitis virus effective amount of at least one substituted-glucamine compound of Formula I or a pharmaceutically acceptable salt thereof:
The compound of Formula I corresponds to the structure: 
wherein:
R and R5 are independently selected from the group consisting of H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkylt cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl, heteroarylakenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, hydroxyalkylcarbonyl, amino(alkyl), alkanoyl(amino)alkyl, (amino)carbonylalkyl, hydroxysulfonealkyl, (amino)carbonylaminoalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl, cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl, tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl, bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl, tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl, cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl, aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl, aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl, heterocycloalkenylcarbonyl, heteroarylakenylcarbonyl, heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl, aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl, and haloalkoxyalkynylcarbonyl, hydroxysulfonealkylcarbonyl, R7 or R8, wherein
R7=R1X1 (R2X2)m(R3X3)n(R4X4)pR13;
R8=R9X9(R10X10)q(R11X11)r(R12X12)R13 
R1 and R9 are independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R2, R3, R4, R10, R11, R12 and R13 are independently selected from the group consisting of alkylene, alkenylene, alkynylene or haloalkylene;
X1, X2, X3, X4, X9, X10, X11 and X12 are independently oxygen, sulfur, sulfoxide or sulfone;
m, n, p, q, r and s are independently 0, 1, 2 or 3;
m+n+pxe2x89xa63.
q+r+sxe2x89xa63
A, B, C, D and E are independently hydrido, lower alkyl or acyl;
A and B taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
B and C taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
C and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
D and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring.
In a second aspect, the present invention provides a method for treating a hepatitis virus infection in a mammal, comprising administering to said mammal an antiviral composition consisting essentially of an antiviral effective amount of at least one substituted-glucamine compound of Formula I as defined above, or a pharmaceutically acceptable salt thereof. In a third aspect, the present invention provides a method for treating a hepatitis virus infection in a mammal, comprising administering to said mammal an antiviral composition containing an antiviral effective amount of at least one substituted-glucamine compound of Formula I, as defined above or a pharmaceutically acceptable salt thereof, as above, substantially exclusive of the administration of any antiviral agent comprising a nucleoside, a nucleotide, an immunomodulator, or an immunostimulant.
In a fourth aspect, the present invention provides a method for treating a hepatitis virus infection in a mammal, consisting essentially of administering to said mammal an antiviral composition comprising an antiviral effective amount of at least one substituted-glucamine compound of Formula I, as defined above, or a pharmaceutically acceptable salt thereof, as above. In this method, the antiviral composition can consist essentially of an antiviral effective amount of the substituted-glucamine compound of Formula I, or a pharmaceutically acceptable salt thereof.
In a fifth aspect, the present invention provides a method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of at least one substituted-glucamine compound of Formula I, as defined above, or a pharmaceutically acceptable salt thereof and a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, an immunomodulator, an immunostimulant, and mixtures thereof, wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.
In a sixth aspect the invention is directed to a method for treating a hepatitis virus infection in a mammal, consisting essentially of administering to said mammal an anti-hepatitis virus effective amount of an antiviral composition consisting essentially of at least one N-substituted-glucamine compound of Formula I or a pharmaceutically acceptable salt thereof.
In a seventh aspect, the invention is directed to a method consisting essentially of administering to said mammal an anti-hepatitis virus effective amount of a composition containing an anti-viral agent, said anti-viral agent consisting essentially of at least one N-substituted-glucamine compound of Formula I or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal from about 0.1 mg/kg/day to about 100 mg/kg/day of at least one N-substituted-glucamine compound of Formula I, as above, and from about 0.1 mg/person/day to about 500 mg/person/day of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and a mixture thereof.
In another aspect, the present invention provides a pharmaceutical composition, consisting essentially of an antiviral effective amount of at least one N-substituted-glucamine compound of Formula I, as defined above, or a pharmaceutically acceptable salt thereof, as above and a pharmaceutically acceptable carrier, excipient, or diluent.
In another aspect, the present invention provides a pharmaceutical composition, containing an antiviral effective amount of at least substituted-glucamine compound of Formula I or a pharmaceutically acceptable salt thereof, as above, substantially exclusive of any antiviral agent comprising a nucleoside, a nucleotide, an immunomodulator, or an immunostimulant and a pharmaceutically acceptable carrier, diluent, or excipient.
In another aspect, the present invention provides a composition, comprising at least substituted-glucamine compound of Formula I, as above, and an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, an immunomodulator, an immunostimulant, and mixtures thereof.
In another aspect, the present invention provides a pharmaceutical composition, comprising a first amount of at least one substituted-glucamine compound of Formula I, as above, a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, an immunomodulator, and immunostimulant, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein said first and second amounts of said compounds together comprise an antiviral effective amount of said compounds.
In yet a further aspect, the present invention provides a pharmaceutical composition for treating a hepatitis B virus infection in a mammal, comprising from about 0.1 mg to about 100 mg of at least one substituted-glucamine compound of Formula I, as above, and from about 0.1 mg to about 500 mg of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
Also provided is a pharmaceutical composition for treating a hepatitis B virus infection in a human patient, comprising from about 0.1 mg to about 100 mg of N-(n-nonenyl)-glucamine, from about 0.1 mg to about 500 mg of (xe2x88x92)-2xe2x80x2-deoxy-3xe2x80x2-thiocytidine-5xe2x80x2-triphosphate, and a pharmaceutically acceptable carrier, diluent, or excipient.
In another aspect, nucleosides and nucleotides and analogs such as AZT that inhibit sugar processing in addition to or instead of interfering with DNA or RNA are of special interest for use in combination therapy with iminosugars of this invention and for us in pharmaceutical formulations with the iminosugars disclosed herein. We intend that compounds such as AZT are useful in combination with the iminosugars disclosed herein for the treatment of diseases described with regard to the various aspects of this invention.
Each of the methods of the invention as described hereinabove is effective for treating various forms of infectious hepatitis. Forms of hepatitis which can be treated by administration of the above-described imino sugars include hepatitis B, hepatitis C, hepatitis delta, hepatitis E, hepatitis F and hepatitis G. The methods of the invention are particularly suited and preferred for the treatment of hepatitis B and hepatitis C.
In another aspect, the present invention provides intermediates useful for the preparation of substituted-glucamine compounds or a salt thereof used alone or in combination in the treatment of Hepatitis B infection.
Also provided is a salt, comprising an anti-hepatitis effective amount of an N-substituted-glucamine compound of Formula I, as described above, and a nucleoside having an acidic moiety or a nucleotide.
Also provided is a compound, comprising an N-substituted-glucamine compound selected from:
The compound of Formula I corresponds to the structure: 
wherein: R is aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, hydroxyalkylcarbonyl, amino(alkyl), alkanoyl(amino)alkyl, (amino)carbonylalkyl, hydroxysulfonealkyl, (amino)carbonylaminoalkyl, or R5, wherein
R7=R1X1(R2X2)m(R3X3)n(R4X4)pR13;
R8=R9X9(R10X10)q(R11X11)r(R12X12) R13 
R1 and R9 are independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R2, R3, R4, R10, R11, R12 and R13 are independently selected from the group consisting of alkylene, alkenylene, alkynylene or haloalkylene;
X1, X2, X3, X4, X9, X10, X11 and X12 are independently oxygen, sulfur, sulfoxide or sulfone;
m, n, p, q, r and s are independently 0, 1, 2 or 3;
m+n+pxe2x89xa63
q+r+sxe2x89xa63
A, B, C, D and E are independently hydrido, lower alkyl or acyl;
A and B taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
B and C taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
C and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
D and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
wherein the main chain in R or R5 contains between one and twenty atoms;
the main chain of each of R7 and R8 contains between four and twenty atoms and either of R1X1 or R9X9; provided that R and R5 are not both hydrido.